Mast Cell Disease Urticaria Pigmentosa

Synonyms:

Etiology: Associations:

Clinical:

Histology:

IHC repertoire: Staging: Prognosis: Adverse variables: Treatment:

Urticaria pigmentosa, telangiectasia macularis eruptive perstans, mastocytoma, mastocytosis

Unknown

Nausea, vomiting, diarrhea, syncope, mast cell leukemia, other hematologic malignancies

Papules or nodules with or without associated hyperpigmentation and telangiectasia; positive Darier's sign

Increased dermal mast cells perivascular or as tumor nodules, basilar hyperpigmentation, vascular ectasia CD117 (c-kit) and mast cell tryptase positive Bone marrow involvement conveys poor prognosis Varies with subtype of disease; benign in children Bone marrow involvement

Chemotherapy including interferon alfa if bone marrow involvement; topical steroids; close clinical follow-up in patients with adult-onset disease

Cutaneous mast cell disease has several different manifestations. It can present during the neonatal period or throughout life. Different age populations generally develop different clinical manifestations and different associated conditions. It is the systemic form of mastocy-tosis in adults that has the most potentially severe complications. It has been estimated that from 15% to 50% of patients with adult-onset mast cell disease will have systemic involvement (1,2). However, for the sake of completeness, the other variants of this disease spectrum will also be considered. Urticaria pigmentosa is the global term for all conditions that are characterized by increased numbers of mast cells within the dermis. There is no gender predilection.

Mast cell disease in childhood is only rarely associated with systemic disease (less than 2% of the time in one series). About one-third of all patients with mast cell disease are less than 15 years old (3). The disease resolves spontaneously in two to three years in the vast majority of these patients, by adolescence in virtually all. Children with mast cell disease often have single or a few large, nodular lesions called mastocytomas (Figure 6.1). These most commonly appear within the first three years of life. These lesions urticate easily with stroking (Darier's sign).

Bullous lesions may be present due to extensive papillary dermal edema secondary to histamine release from mast cells. Vesicles do not generally occur as part of cutaneous mast cell disease in patients older than 10 years of age. Rarely, children with diffuse mast cell disease may present with erythroderma (Figure 6.2). Despite the absence of systemic disease, these children are at risk for hypotension, shock, and even death.

Adults with mast cell disease are more likely to present with a widely scattered macular eruption. Individual lesions are often red-brown or hyperpigmented. The lesions are randomly distributed and generalized, but are accentuated on the chest. Petechiae and ecchymoses may occur. Depending upon the mast cell burden within each lesion, an urticarial reaction can be elicited by gently stroking these lesions. Pruritus is the most common symptom. Less commonly, nausea, vomiting, diarrhea, and abdominal pain may be reported. These symptoms occur in patients with limited cutaneous disease as frequently as those with systemic involvement. One type of adult-onset form of the disease is known as telangiectasia macularis eruptive perstans (TMEP). In this variant, abundant hyperpigmented 2-6-mm macules are present on the back and chest in concert with telangiectasias. Pru-

Mastocytoma Tosis
Figure 6.1. Erythematous/tan plaque of mastocytosis in a child.

ritis and urtication are not common. It is currently not possible to distinguish adult patients with disease limited to the skin from those with systemic disease based purely on the cutaneous disease. There is no difference in the age of presentation between those with and without systemic involvement. The mean age of presentation is in the fourth decade. Systemic disease presents much later, often with as much as 20 years separating these findings from the initial cutaneous presentation (3). Patients with systemic disease may remain alive with persistent disease for many years, or may succumb to their illness.

In adults with cutaneous mast cell disease, hepato-splenomegaly is often seen in addition to the macular, hyperpigmented eruption. Lymph node involvement is not uncommon. Osteoblastic lesions can be detected with radiographs. The bone marrow is the most frequently involved extracutaneous site. Eosinophilia is present in 15% of all patients with systemic disease. In these patients, pancytopenia may be present and a bone marrow biopsy and aspiration is necessary to eliminate the presence of mastocytosis or leukemia (mast cell leukemia or chronic myelogenous leukemia). Leukemia is reported to develop in 4%-5% of patients with systemic mastocytosis (4). Involvement of the gastrointestinal tract has been reported but is very uncommon. Increased serum tryptase and increased urinary levels of i-methyl histamine may also be detected in these patients (5).

The histologic findings in child-onset mast cell disease include a very dense dermal infiltrate of mast cells, often filling the entire dermis and extending into the subcutaneous fat. In some cases, prominent papillary dermal edema leads to a subepidermal bulla, correlating with the blisters encountered clinically.

The histologic findings in adult-onset mast cell disease fall into two general categories. Mast cells may be distributed in a perivascular pattern or diffusely (Figure 6.3A and 6.3B).

Neither pattern is predictive of systemic involvement, though the superficial perivascular pattern is more common (3). The number of perivascular mast cells varies widely, but in most cases is relatively slight, with only a minimal increase in cellularity over physiologic levels.

Urticaria Pigmentosa
Figure 6.2. Erythroderma with islands of sparring and hepato-splenomegaly associated with parenchymal organ infiltration in systemic mastocytosis.

Figure 6.3. (A) Low power photomicrograph depicting superficial dermal infiltrate of mastocytosis. (B) Low power photomicrograph depicting superficial dermal infiltrate of mastocytosis in adult T.M.E.P.

Figure 6.3. (A) Low power photomicrograph depicting superficial dermal infiltrate of mastocytosis. (B) Low power photomicrograph depicting superficial dermal infiltrate of mastocytosis in adult T.M.E.P.

Urticaria Pigmentosa Histopathology
A
Mast Cells Dermis

Morphometric point counting has suggested that while the absolute numbers may be small, there is a nine-to-160-fold increase in numbers of mast cells in these cases compared with normal patients (6). Dense diffuse infiltrates within the papillary dermis are encountered less commonly (Figure 6.4).

In these cases, prominent nuclear atypia and presence of nucleoli and multinucleation may be present; however, these findings do not associate invariably with systemic involvement. Mitotic activity is rare in all cases of mast cell disease (Figure 6.5).

In one study, electron microscopy suggested that mast cells from patients with systemic disease are larger, and have more cytoplasm and larger cytoplasmic granules (7). In biopsies from both patterns, an admixture of lymphocytes and eosinophils are present within

Urticaria Pigmentosa Histopathology
Figure 6.4. Medium power photomicrograph depicting uniform population of epithelioid cells within the superficial dermis.

the dermis. In more subtle cases, mast cell numbers can be better assessed with special stains such as toluidine blue or Giemsa's stains, or more specifically, staining with CD117 (c-kit) or mast cell tryptase (Figure 6.6).

Bone marrow involvement with mast cell disease may be very focal and a negative biopsy does not guarantee limited cutaneous disease (3). Conversely, skin involve ment is not present in all cases of systemic mast cell disease (8,9).

Treatment options vary with the extent of disease. Cutaneous lesions can be watched or treated with topical steroids or even surgical excision of limited lesions. More extensive disease requires topical steroids, antihistamines, chemotherapy, interferon, and ultraviolet light therapy. None of these options are entirely effective.

Generalized Animal Cell High Power
Figure 6.5. High power photomicrograph depicting uniform population of rounded cells possessing oval nuclei with ampho-philic staining cytoplasm.

Figure 6.6. Giesma stains reveal metachromatic staining of cytoplasmic granules within mast cells.

Figure 6.6. Giesma stains reveal metachromatic staining of cytoplasmic granules within mast cells.

Metachromatic Granules Urine
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